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Stimulation of Entorhinal Cortex Promotes Adult Neurogenesis and Facilitates Spatial Memory
Open accessAbstract
Deep brain stimulation (DBS) is an established therapeutic modality for the treatment of movement disorders and an emerging therapeutic approach for the treatment of disorders of mood and thought. For example, recently we have shown that DBS of the fornix may ameliorate cognitive decline associated with dementia. However, like other applications of DBS, the mechanisms mediating these clinical effects are unknown. As DBS modulates neurophysiological activity in targeted brain regions, DBS might influence cognitive function via activity-dependent regulation of hippocampal neurogenesis. Using stimulation parameters analogous to clinical high-frequency DBS, here we addressed this question in mice. We found that acute stimulation of the entorhinal cortex (EC) transiently promoted proliferation in the dentate gyrus (DG). Cells generated as a consequence of stimulation differentiated into neurons, survived for at least several weeks, and acquired normal dentate granule cell (DGC) morphology. Importantly, stimulation-induced promotion of neurogenesis was limited to the DG and not associated with changes in apoptotic cell death. Using immunohistochemical approaches, we found that, once sufficiently mature, these stimulation-induced neurons integrated into hippocampal circuits supporting water-maze memory. Finally, formation of water-maze memory was facilitated 6 weeks (but not 1 week) after bilateral stimulation of the EC. The delay-dependent nature of these effects matches the maturation-dependent integration of adult-generated DGCs into dentate circuits supporting water-maze memory. Furthermore, because the beneficial effects of EC stimulation were prevented by blocking neurogenesis, this suggests a causal relationship between stimulation-induced promotion of adult neurogenesis and enhanced spatial memory.
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“Proliferation of newborn neurons in the dentate gyrus increases in response to direct hippocampal stimulation as well as processes stimulating the hippocampus, such as exercise, spatial learning, and an enriched environment [14–16].”
From MiR-338-3p regulates neuronal maturation and suppresses glioblastoma proliferation. (2017) · cites this paper as [15]
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“and to enhance neurogenesis in the dentate gyrus of the hippocampus”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Stone et al., 2011
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Metadata
- Authors
- Stone, S. S. D., Teixeira, C. M., DeVito, L. M., Zaslavsky, K., Josselyn, S. A., Lozano, A. M., & Frankland, P. W.
- Affiliations
- Hospital for Sick Children (CA)
- Universidade do Porto (PT)
- University of Toronto (CA)
- Corresponding author
- Frankland, Paul W.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-09-21
- Volume
- 31
- Issue
- 38
- Pages
- 13469-13484
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6623309
- OpenAlex
- W2132668024
- Cited by
- 384
- References
- 68
- Citations by year
- 2026: 12 · 2025: 8 · 2024: 18 · 2023: 16 · 2022: 24 · 2021: 32 · 2020: 27 · 2019: 24 · 2018: 27 · 2017: 21 · 2016: 38 · 2015: 41 · 2014: 24 · 2013: 30 · 2012: 39
- FWCI
- 10.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Toronto
- Canadian Institutes of Health Research (MOP- 86762, 102234_1)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
- Keywords
- entorhinal cortex, deep brain stimulation, adult neurogenesis, dentate gyrus, dentate gyrus granule cells, spatial memory, cell proliferation, neuronal differentiation, apoptosis
- MeSH terms
- Animals, Cell Survival, Memory, Mice, Inbred Strains, Neural Pathways, Neurons, Spatial Behavior, Time Factors, Apoptosis, Entorhinal Cortex, Maze Learning, Dentate Gyrus, Deep Brain Stimulation, Mice, Neurogenesis, Neuroanatomical Tract-Tracing Techniques
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